ABSTRACT Kaposi's sarcoma (KS) is a highly prevalent malignancy in sub-Saharan Africa. This cancer, with Kaposi's sarcoma herpesvirus (KSHV) as the etiologic agent, is at increased incidence in HIV-1 infected patients despite antiretroviral (ART) suppression of HIV-1 viral load. It also occurs as an aggressive tumor in the HIV-negative population. Our team has been studying KS and KSHV transmission in KS endemic countries and we have shown that KSHV infection is acquired predominantly in early childhood, HIV-1 infection is a major risk factor, and that mucosal exposure to infectious saliva is the likely mechanism of transmission. More recently, our results from Zambia and Tanzania demonstrated that high titer neutralizing Ab responses (nAb) develop primarily in individuals with symptomatic KS as opposed to infected asymptomatic individuals, suggesting that nAb is not a correlate of KS protection. Thus, much like in the HIV-1 virus-host interaction, it appears that KSHV nAb cannot prevent disease after long-term chronic infection. However, the prophylactic capacity of passively administered broadly nAb has been demonstrated in HIV-1/SIV infectious challenge models; whereas, the ability of pre-existing nAb to prevent KSHV transmission is untested. In addition, while the in vitro KSHV entry process has been studied in some depth, the precise viral and cellular interactions involved in KSHV at the tissue level, have not been clearly elucidated. In part, this knowledge gap results from the lack of an in vivo model of human KSHV transmission. The proposed project applies our team's long-term experience with KS, KSHV, human KSHV Ab responses, and KSHV infection in a humanized mouse model that we have developed, to address the knowledge gap posed by KSHV transmission and dissemination. Our overall objective is to identify immune response(s) that can protect against KSHV infection and transmission, and thereby, prevent KS. Our hypothesis is that KSHV nAb can be protective against KSHV transmission in ex vivo human organotypic tissue models and in a humanized mouse model of KSHV infection. The hypothesis will be tested with 3 specific aims: 1) Develop organotypic oral and vaginal epithelial culture models to understand KSHV transmission dynamics and to test whether sera with high nAb titer prevents trans-epithelial KSHV infection; 2) test whether KSHV nAb is protective in a humanized BLT-mouse model of mucosal and blood exposure, infection and dissemination of KHSV, and 3) isolation of human monoclonal KSHV nAb and characterization of their impact on KSHV transmission. This project will clarify the mechanisms of KSHV transmission and dissemination, and lay the foundations for strategies to develop a vaccine to prevent KSHV infection. Ultimately, such studies will expand our capacity to prevent KSHV infection and associated neoplasms.